rs1799921

Variant names:

• chr5-63961638-T-C
• rs1799921
• NM_000524.4:c.82A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000524.4(HTR1A):​c.82A>G​(p.Ile28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,872 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (121 hom.)
• Consequence: HTR1A NM_000524.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.833
• Publications: 26 publications found

Genes affected

HTR1A (HGNC:5286): (5-hydroxytryptamine receptor 1A) This gene encodes a G protein-coupled receptor for 5-hydroxytryptamine (serotonin), and belongs to the 5-hydroxytryptamine receptor subfamily. Serotonin has been implicated in a number of physiologic processes and pathologic conditions. Inactivation of this gene in mice results in behavior consistent with an increased anxiety and stress response. Mutation in the promoter of this gene has been associated with menstrual cycle-dependent periodic fevers. [provided by RefSeq, Jun 2012]

HTR1A Gene-Disease associations (from GenCC):

• menstrual cycle-dependent periodic fever

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000248285 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005230218).
• BP6: Variant 5-63961638-T-C is Benign according to our data. Variant chr5-63961638-T-C is described in ClinVar as Benign. ClinVar VariationId is 771709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0117 (17107/1461554) while in subpopulation MID AF = 0.0187 (108/5768). AF 95% confidence interval is 0.0159. There are 121 homozygotes in GnomAdExome4. There are 8438 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR1A	NM_000524.4	c.82A>G	p.Ile28Val	missense_variant	Exon 1 of 1	ENST00000323865.5	NP_000515.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR1A	ENST00000323865.5	c.82A>G	p.Ile28Val	missense_variant	Exon 1 of 1	6	NM_000524.4	ENSP00000316244.4
HTR1A	ENST00000506598.1	c.82A>G	p.Ile28Val	missense_variant	Exon 2 of 2	4		ENSP00000423433.1
ENSG00000248285	ENST00000502882.1	n.97-3623A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1418 AN: 152200 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00940 AC: 2317 AN: 246554 AF XY: 0.00971

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00832

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0117 AC: 17107 AN: 1461554 Hom.: 121 Cov.: 31 AF XY: 0.0116 AC XY: 8438 AN XY: 727052

African (AFR) AF: 0.00152 AC: 51 AN: 33480

American (AMR) AF: 0.00863 AC: 386 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 262 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00568 AC: 490 AN: 86258

European-Finnish (FIN) AF: 0.0116 AC: 616 AN: 53090

Middle Eastern (MID) AF: 0.0187 AC: 108 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14524 AN: 1112006

Other (OTH) AF: 0.0111 AC: 670 AN: 60392

GnomAD4 genome AF: 0.00930 AC: 1417 AN: 152318 Hom.: 9 Cov.: 33 AF XY: 0.00988 AC XY: 736 AN XY: 74474

African (AFR) AF: 0.00257 AC: 107 AN: 41600

American (AMR) AF: 0.0133 AC: 203 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 857 AN: 68032

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0116 Hom.: 22

Bravo AF: 0.00901

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0134 AC: 115

ExAC AF: 0.00884 AC: 1072

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HTR1A: BP4, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.1
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.83
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.049
Sift	Benign	0.59	T;T
Sift4G	Benign	0.52	T;.
Polyphen		0.0	B;.
Vest4		0.042
MVP		0.24
MPC		0.53
ClinPred		0.00030	T
GERP RS		1.2
Varity_R		0.021
gMVP		0.14
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1799921; hg19: chr5-63257465; COSMIC: COSV99072612;